Rolf Holle

Common variants in myocardial Ion channel genes modify the QT interval in the general population : Results from the KORA study

Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P=0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P=0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, −1.9 ms/allele, P=0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P=0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.951 of trait variance (P<0.00005). These results confirm previous heritability studies indicating that repolarization is a complex trait with a significant heritable component and demonstrate that high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small.

Incidence of Type 2 diabetes in the elderly German population and the effect of clinical and lifestyle risk factors: KORA S4/F4 cohort study

Aims  To determine the incidence of Type 2 diabetes in an elderly population in Germany and its association with clinical and lifestyle factors.

DNA methylation-based measures of biological age: meta-analysis predicting time to death.

Estimates of biological age based on DNA methylation patterns, often referred to as “epigenetic age”, “DNAm age”, have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2×10−9), independent of chronological age, even after adjusting for additional risk factors (p<5.4×10−4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5×10−43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.

Official statistics and claims data records indicate non-response and recall bias within survey-based estimates of health care utilization in the older population

BackgroundThe validity of survey-based health care utilization estimates in the older population has been poorly researched. Owing to data protection legislation and a great number of different health care insurance providers, the assessment of recall and non-response bias is challenging to impossible in many countries. The objective of our study was to compare estimates from a population-based study in older German adults with external secondary data.MethodsWe used data from the German KORA-Age study, which included 4,127 people aged 65–94 years. Self-report questions covered the utilization of long-term care services, inpatient services, outpatient services, and pharmaceuticals. We calculated age- and sex-standardized mean utilization rates in each domain and compared them with the corresponding estimates derived from official statistics and independent statutory health insurance data.ResultsThe KORA-Age study underestimated the use of long-term care services (−52%), in-hospital days (−21%) and physician visits (−70%). In contrast, the assessment of drug consumption by postal self-report questionnaires yielded similar estimates to the analysis of insurance claims data (−9%).ConclusionSurvey estimates based on self-report tend to underestimate true health care utilization in the older population. Direct validation studies are needed to disentangle the impact of recall and non-response bias.

Risk factors associated with a low glomerular filtration rate in primary aldosteronism.

CONTEXT Primary aldosteronism (PA) is associated with vascular end organ damage. OBJECTIVE We evaluated the newly established German Conns Registry for evidence of renal impairment and compared the data with those from hypertensive subjects of a population-based survey. DESIGN We conducted a case-control study. PATIENTS AND CONTROLS A total of 408 patients with PA from the Conns registry treated in five German centers were matched for age, sex, and body mass index in a 1:1 ratio with 408 hypertensive control subjects from the population-based F3 survey of the Kooperative Gesundheitsforschung in the region of Augsburg (KORA). MAIN OUTCOME MEASURES We measured serum creatinine and calculated glomerular filtration rate (GFR). RESULTS The percentage of patients with a serum creatinine concentration above the normal range of 1.25 mg/dl was higher in patients with PA than in hypertensive controls (29 vs. 10%; P < 0.001). Regression analysis showed that age, male sex, low potassium, and high aldosterone concentrations were independent predictors of a lower GFR. Adrenalectomy reduced systolic blood pressure from a mean of 160 to 144 mm Hg. In parallel, we observed an increase in serum creatinine and a decrease of GFR from 71 to 64 ml/min (P < 0.001). A similar trend was seen after spironolactone treatment. CONCLUSIONS In a large cohort of patients with PA, markers of disease activity such as plasma aldosterone and serum potassium are independent predictors of a lower GFR. Specific interventions, such as adrenalectomy or spironolactone treatment, are associated with a further decline in GFR.

Quality of life several years after myocardial infarction: comparing the MONICA/KORA registry to the general population†

AIMS The aim of this study was to assess the impact of myocardial infarction (MI) on health-related quality of life (HRQL) in MI survivors measured by EuroQol (EQ-5D) and to compare it with the general population. METHODS AND RESULTS A follow-up study of all MI survivors included in the MONICA/KORA registry was performed. About 2950 (67.1%) patients responded. Moderate or severe problems were most frequent in EQ-5D dimension pain/discomfort (55.0%), anxiety/depression (29.2%), and mobility (27.9%). Mean EQ VAS score was 65.8 (SD 18.5). Main predictors of lower HRQL included older age, diabetes, increasing body mass index, current smoking, and experience of re-infarction. Type of revascularizational treatment showed no impact on HRQL. Compared with the general population, adjusted EQ VAS was 6.2 (95% confidence interval 3.4-8.9) points lower in 45-year-old MI patients converging with growing age up to the age of 80. With regard to HRQL dimensions, MI survivors had a significantly higher risk of incurring problems in the dimension pain/discomfort, usual activities, and especially in anxiety/depression which was more pronounced in younger age. Mobility was the single dimension, in which MI showed an inverse effect. CONCLUSION MI is combined with significant reduction in HRQL compared with the general population. The main impairments occur in the dimension pain/discomfort, usual activities, and particularly anxiety/depression. The relative impairment decreases with higher ages.

Observational Study Mortality in Treated Primary Aldosteronism The German Conn's Registry

In comparison with essential hypertension, primary aldosteronism (PA) is associated with an increased risk of cardiovascular morbidity. To date, no data on mortality have been published. We assessed mortality of patients treated for PA within the German Conns registry and identified risk factors for adverse outcome in a case-control study. Patients with confirmed PA treated in 3 university centers in Germany since 1994 were included in the analysis. All of the patients were contacted in 2009 and 2010 to verify life status. Subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg served as controls. Final analyses were based on 600 normotensive controls, 600 hypertensive controls, and 300 patients with PA. Kaplan-Meyer survival curves were calculated for both cohorts. Ten-year overall survival was 95% in normotensive controls, 90% in hypertensive controls, and 90% in patients with PA (P value not significant). In multivariate analysis, age (hazard ratio, 1.09 per year [95% CI, 1.03–1.14]), angina pectoris (hazard ratio, 3.6 [95% CI, 1.04–12.04]), and diabetes mellitus (hazard ratio, 2.55 [95% CI, 1.07–6.09]) were associated with an increase in all-cause mortality, whereas hypokalemia (hazard ratio, 0.41 per mmol/L [95% CI, 0.17–0.99]) was associated with reduced mortality. Cardiovascular mortality was the main cause of death in PA (50% versus 34% in hypertensive controls; P<0.05). These data indicate that cardiovascular mortality is increased in patients treated for PA, whereas all-cause mortality is not different from matched hypertensive controls.

Regional differences in the prevalence of known Type 2 diabetes mellitus in 45–74 years old individuals: Results from six population‐based studies in Germany (DIAB‐CORE Consortium)

Diabet. Med. 29, e88–e95 (2012)

Multimorbidity and health-related quality of life in the older population: results from the German KORA-Age study

BackgroundMultimorbidity in the older population is well acknowledged to negatively affect health-related quality of life (HRQL). Several studies have examined the independent effects of single diseases; however, little research has focused on interaction between diseases. The purpose of this study was to assess the impact of six self-reported major conditions and their combinations on HRQL measured by the EQ-5D.MethodsThe EQ-5D was administered in the population-based KORA-Age study of 4,565 Germans aged 65 years or older. A generalised additive regression model was used to assess the effects of chronic conditions on HRQL and to account for the nonlinear associations with age and body mass index (BMI). Disease interactions were identified by a forward variable selection method.ResultsThe conditions with the greatest negative impact on the EQ-5D index were the history of a stroke (regression coefficient -11.3, p < 0.0001) and chronic bronchitis (regression coefficient -8.1, p < 0.0001). Patients with both diabetes and coronary disorders showed more impaired HRQL than could be expected from their separate effects (coefficient of interaction term -8.1, p < 0.0001). A synergistic effect on HRQL was also found for the combination of coronary disorders and stroke. The effect of BMI on the mean EQ-5D index was inverse U-shaped with a maximum at around 24.8 kg/m2.ConclusionsThere are important interactions between coronary problems, diabetes mellitus, and the history of a stroke that negatively affect HRQL in the older German population. Not only high but also low BMI is associated with impairments in health status.

Subclinical inflammation and diabetic polyneuropathy: MONICA/KORA Survey F3 (Augsburg, Germany).

OBJECTIVE Subclinical inflammation represents a risk factor of type 2 diabetes and several diabetes complications, but data on diabetic neuropathies are scarce. Therefore, we investigated whether circulating concentrations of acute-phase proteins, cytokines, and chemokines differ among diabetic patients with or without diabetic polyneuropathy. RESEARCH DESIGN AND METHODS We measured 10 markers of subclinical inflammation in 227 type 2 diabetic patients with diabetic polyneuropathy who participated in the population-based MONICA/KORA Survey F3 (2004–2005; Augsburg, Germany). Diabetic polyneuropathy was diagnosed using the Michigan Neuropathy Screening Instrument (MNSI). RESULTS After adjustment for multiple confounders, high levels of C-reactive protein and interleukin (IL)-6 were most consistently associated with diabetic polyneuropathy, high MNSI score, and specific neuropathic deficits, whereas some inverse associations were seen for IL-18. CONCLUSIONS This study shows that subclinical inflammation is associated with diabetic polyneuropathy and neuropathic impairments. This association appears rather specific because only certain immune mediators and impairments are involved.